Mice Lacking the Fructose Transporter Glut5 Exhibit Excessive Androgens and Reduced Sperm Motility

Overconsumption of fructose is linked to metabolic diseases, which are often associated with reduced fertility. GLUT5 is the most specific fructose transporter. To investigate its role in the testes, we analyzed the male reproductive phenotype of transgenic male mice deficient in GLUT5 (GLUT5-/- or GLUT5 knockout [KO] mice). Glut5 expression was shown in Leydig cells and germ cells, from primary spermatocytes to spermatozoa. We found reduced intratesticular fructose and pyruvate concentrations in GLUT5-/- mice. These mice exhibited 30% lower litter sizes compared with control mice. Histological analysis of the testes revealed some seminiferous tubules with a "Sertoli cell-only" phenotype, although spermatogenesis occurred normally in most tubules. Reduced fertility in GLUT5 KO mice was linked to lower sperm production and impaired sperm quality. Spermatozoa from these mice displayed reduced motility, head abnormalities, and a diminished acrosome reaction, which was associated with reduced cyclic adenosine monophosphate content and impaired phosphorylation of protein kinase A substrates in the acrosome. Unexpectedly, androgen production in GLUT5 KO mice was 3-fold higher than in controls, despite unchanged luteinizing hormone levels. Electron microscopy of Leydig cells revealed a highly developed smooth endoplasmic reticulum, increased lipid droplets, and abnormal mitochondrial structures, suggesting disrupted mitochondrial dynamics. Proteomic analysis identified 155 deregulated proteins in the testicular tissue of GLUT5 KO mice, nearly half of which were associated with sperm motility, germ cell morphology, glycolysis, mitochondrial dynamics, and oxidative stress. In conclusion, the absence of the specific fructose transporter GLUT5 reduced testicular fructose content and led to an asthenozoospermia phenotype accompanied by hyperandrogenism.